The embodiments described herein relate generally to medical devices and pharmaceutical compositions, and more particularly to a drug product for injection of opioid antagonists, including formulations for naloxone.
Opioid antagonists are medicaments that prevent and/or reverse the effects of opioids. Known opioid antagonists, such as naltrexone and naloxone, can be used, for example, to treat respiratory depression and other indications that result from opioid toxicity. For example, known formulations for naloxone can be used to reverse and/or mitigate the effects of an overdose of a drug containing opioids, such as, for example, heroin. In such situations, it is desirable to deliver the naloxone formulation quickly and in a manner that will produce a rapid onset of action. Accordingly, known formulations of naloxone are often delivered either intranasally or via injection.
The delivery of naloxone intranasally or via injection, however, often involves completing a series of operations that, if not done properly, can limit the effectiveness of the naloxone formulation. For example, prior to delivering the naloxone, the user must first determine whether the patient's symptoms warrant the delivery of naloxone, and then couple a needle (or an atomizer) to a syringe containing the naloxone formulation. After the device is prepared for delivery, the user then selects the region of the body in which the naloxone is to be delivered, and manually produces a force to deliver the naloxone. In some situations, such as, for example, when the patient is in an ambulance or a hospital setting, the user then inserts an intravenous catheter to administer the naloxone. Additionally, after the delivery of the naloxone formulation, the user must dispose of the device properly (e.g., to prevent needle sticks in instances where the naloxone is injected) and seek further medical attention for the patient. Accordingly, known formulations of naloxone are often delivered by a healthcare provider in a controlled environment (e.g. a hospital, physician's office, clinic or the like). Access to emergency medical facilities and/or trained health care providers, however, is not always available when an individual is suffering from an overdose. Moreover, because naloxone is often administered during an emergency situation, even experienced and/or trained users may be subject to confusion and/or panic, thereby compromising the delivery of the naloxone formulation.
The use of some known devices for delivering naloxone compositions generally involves a user manually generating a force and/or pressure that is sufficient to convey the naloxone from the device into the body. For example, to deliver naloxone using known syringes, the user manually inserts a needle into the body (e.g., intramuscularly) and following insertion, manually depresses a plunger into the syringe body. The force generated by the user to insert the needle and/or manually depress the plunger, however, can vary depending on the user (e.g., based on a user's strength, comfort level, experience, etc.), thus resulting in undesirable fluctuations in the flow of the naloxone and/or incomplete delivery of the full dose. Such fluctuations and variability can be particularly undesirable when the naloxone is being atomized for intranasal delivery. For example, in some instances, the user may be unable to generate sufficient force to provide the desired flow rate and/or flow characteristics (e.g., for an atomizer) of the naloxone. Moreover, in certain situations, a user could inadvertently insert a needle of a syringe containing a dose of a naloxone composition at an angle relative to a target injection site, which can result in failure to deliver the dose intramuscularly. For example, in some such situations, the dose may be delivered subcutaneously, which can affect the release of the drug into the body and thus, the desired pharmacokinetics (PK) of the naloxone composition. In addition, most manually actuated syringes do not include an automatic retraction of the needle and/or otherwise include a needle covering mechanism that is automatically deployed upon removal of the needle from the body, which can result in inadvertent needle sticks or the like.
To mitigate at least some of the challenges presented above, some known devices such as, for example, autoinjectors, can be arranged to automatically perform some or all of the steps for delivering a dose of an opioid antagonist. Some known autoinjectors, however, deliver a dose at a much faster rate and/or at higher pressures than a manually actuated syringe. The higher pressure and/or faster rate of delivery can result in a difference in the delivery of the drug, thereby affecting the pharmacokinetic characteristics of the drug upon delivery. Similarly stated, changing the mechanism of delivery of a known drug can influence the drug performance. In particular, studies have demonstrated differences in the bioavailability of an injectable drug product between different pharmaceutical delivery technologies (Bennett, Nichols, Rosenblum, & Condry, 1998; Brearly, Priestley, Leighton-Scott, & Christen, 2007; Simons, Gu, Simons, 2001). For example, the study by Bennett et al. investigated midazolam administered by a conventional syringe and needle compared to administration via a jet injection system, and found that the delivery via the jet injector produced peak midazolam plasma concentrations over 30% faster with a significantly greater overall peak level than delivery via the conventional syringe (Bennett, et al., 1998). Similar studies with insulin have demonstrated substantial pharmacokinetic differences between different delivery systems (Kerum, Profozic, Granic, & Skrabalo, 1987; Halle, Lambert, Lindmayer, Menassa, Coutu, Moghrabi, Legendre, Legault, & Lalumiere, 1986; Taylor, Home, & Alberti, 1981). More importantly, there have been reports of undesirable outcomes as a result of choosing the wrong delivery system for the desired clinical response. As one example, the drug peramivir, which was being developed for seasonal flu, failed to meet the primary endpoint in the mid-stage trial “because too-short needles failed to deliver the drug to the muscle in all of the patients” (Biocryst, 2007).
In the “Development of a Novel Approach to Assess Qualitative and Quantitative Dynamics Associated with the Subcutaneous or Intramuscular Administration of Pharmaceuticals and Associated Parenteral Delivery Systems,” the kinematics of an injection by standard manual syringe is compared with an injection by auto-injector. The dispersion of a contrast agent (iohexol) into the body after injection was observed in real-time by the use of computed tomography (CT) scanning. It was found that iohexol delivered subcutaneously by an auto-injector resulted in notable qualitative and quantitative dispersion differences, including a higher rate of iohexol loss from the extravascular tissue, as well as differences in early plasma exposure as compared to a pre-filled syringe delivery system.
Therefore, the effectiveness of a dose of a naloxone composition formulated to be delivered via a manually actuated syringe can be dependent on the pharmacokinetic characteristics associated with the delivery modality.
Thus, a need exists for improved methods and devices for delivering opioid antagonists, such as, for example, devices that provide for at least a partially automatic delivery of naloxone compositions while maintaining, for example, pharmacokinetic characteristics of delivery via a manually actuated syringe.